The present invention relates to novel therapeutic methods and pharmaceutical compositions for treatment and protection of skin damage caused by ultraviolet (UV) radiation. More particularly, the present invention related to methods utilizing and compositions comprising tellurium containing compounds, which prevent the induction of IL-10 produced by exposure to ultraviolet radiation.
Ultraviolet radiation is electromagnetic radiation of a wavelength shorter than that of the visible light, but longer than that of X-rays. It may be subdivided into UVA (315-380 nanometers), UVB (280-315 nanometers) and UVC (less than 280 nanometers.
The most common consequence of ultraviolet exposure is erythema, or sunburn. Severe sunburn is marked by bright pink or even scarlet-colored skin, swelling, blistering, and extreme pain. An extremely severe case may also be accompanied by nausea, fever or chills, and tachycardia (a racing heart beat). Because of water lost through the skin, sunburns can also lead to dehydration. UV damage apparently triggers an increase of several chemical substances, including prostaglandins and histamines, both of which contribute to inflammation.
Sunburn is primarily caused by UVB rays. UVA rays penetrate deeply and do not cause sunburn, but can contribute to the ageing of the skin, DNA damage and possibly skin cancer. UVA rays are absorbed less efficiently by the atmosphere than UVB. Consequently, the ratio of UVA to UVB will increase as the sun gets lower in the sky.
Long-term exposure to UV rays may also result in sun-damaged skin, even in the absence of sunburn. Much of what was once attributed to aging is now known to be caused by sun damage. Old age can bring about roughness, fine wrinkling, and looseness of the skin. Sun-exposed skin, however, is also marked by coarse wrinkling and elastosis, which gives the skin a pebbly, yellowed quality. Both wrinkling and elastosis are caused by damage to collagen fibers in the lowest level of skin, the dermis.
In addition to these effects, sun-exposed skin is also prone to irregular hyperpigmentation and depigmentation, and actinic keratoses, which are rough, red patches of precancerous skin cells.
As a defense against UV radiation, the body tans when exposed to moderate levels of radiation by releasing melanin, which helps to block UV penetration and prevent damage to the vulnerable lower skin tissues.
Suntan (also referred to herein as sun screen and sun block) preparations that partly blocks UV radiation is widely available. Most sunscreens work by use of an organic material that absorbs UV radiation (such as oxybenzone) or an opaque material that reflects UV rays (such as titanium dioxide, zinc oxide), or a combination thereof. Active ingredients allowable by the FDA in sunblocks include p-aminobenzoic acid, avobenzone, cinoxate, dioxybenzone, homosalate, menthyl anthranilate, octocrylene, octyl methoxycinnamate, octyl salicylate, oxybenzone, padimate, phenylbenzimidazole sulfonic acid, sulisobenzone, titanium oxide, trolamine salicylate and zinc oxide.
Solar radiation in the ultraviolet (UV) range, especially UVA and UVB, may also cause suppression of the skin's immune function (Frontiers in Bioscience 2, 1997; 538-551), and may produce a carcinogenic effect. Studies suggest that UVA is important in causing immunosuppression in the skin (Br J Dermatol. 2002; 146:933-937). In one indicator of immunosuppression, UV radiation cripples immunity by diminishing the Langerhans cells' number and function (Proc Natl Acad Sci USA. 1997, 94:5255-5260; J Biomed Biotechnol. 2001; 1:5-6). Langerhans cells exposed to UV in vitro lose the ability to present antigens to T cells (Proc Natl Acad Sci USA. 1997; 94:5255-5260). In the skin, Langerhans cells are inhibited by the release of cytokines, such as IL-10. UV irradiation can also convert normal skin chromophores into agents that are immunosuppressive, such as the conversion of transurocanic acid to cis-urocanic acid (Frontiers in Bioscience 2, 1997; 538-551).
Immune-response modifiers have been found to induce activation of Toll-like receptors, which leads to production of cytokines and chemokines, such as INF-[alpha], TNF-[alpha], IL-12, MCP-1, and MIP-1[alpha] (J Exp Med. 2001; 194:863-870; J Interferon Cytokine Res. 1995; 15:537-545). The chemokines attract immune cells to the site of application, and the cytokines cause activation of immune cells. Toll agonists have been found to promote cytokine and chemokine release from dendritic cells that reside in the dermis and the epidermis (J Exp Med. 2001; 194:863-870). Activation of immune cells and release of cytokines by these dendritic cells can rally the immune system back into action, overcoming the Langerhans cell deficit (J Invest Dermatol. 2000; 114:135-141).
Acute UV damage to keratinocytes usually leads to activation of the tumor-suppressing gene p53, which is responsible for induction of DNA repair and apoptosis (Frontiers in Bioscience 2, 1997; 538-551). When the UV exposure is chronic, however, errors associated with DNA repair and/or replication can result in mutations in the p53 gene. The damage caused involves chemical bonding of adjacent pyrimidine bases in the form of dimers. These dimers are of 2 main types: pyrimidine pyrimidone photoproducts between adjacent pyrimidine residues, and cyclobutane dimers between adjacent thymine or cytosine residues. The p53 mutation in keratinocytes plays a key role in the process of carcinogenesis in the skin. In addition to the p53 gene, mutations in another tumor-suppressing gene, the patched (PTCH) gene, seem to be implicated in the formation of skin carcinomas (Br J Dermatol. 2002; 146(suppl 61):17-19).
The efficacy of topically applied sunscreens is determined by their ability to inhibit UV-induced erythema. Sunscreens have been assumed to also provide protection against UV-induced carcinogenesis. However, UV exposure causes characteristic immunological alterations in the skin, which might be of direct pathogenic relevance to UV-induced carcinogenesis. Since, according to the present understanding of the immunological and molecular events leading to carcinogenesis of the skin, measurement of UV-induced erythema and vasodilation appears insufficient, so the prevention of UV-induced erythema might, in fact, be biologically irrelevant as an indicator of protection against UV-induced skin cancer.
Various tellurium compounds have been described in the art as having immunomodulating properties. A particularly effective family of tellurium-containing compounds is taught, for example, in U.S. Pat. Nos. 4,752,614; 4,761,490; 4,764,461 and 4,929,739, whereby another effective family, represented by a compound called SAS, is taught, for example, in a recently filed U.S. Provisional Patent Application No. 60/610,660, which are all incorporated by reference as if fully set forth herein. The immunomodulating properties of this family of tellurium-containing compounds is described, for example, in U.S. Pat. Nos. 4,962,207, 5,093,135, 5,102,908 and 5,213,899, which are all incorporated by reference as if fully set forth herein.
One of the most promising compounds described in these patents is ammonium trichloro(dioxyethylene-O,O′) tellurate, which is also referred to herein and in the art as AS101. AS101, as a representative example of the family of tellurium-containing compound discussed hereinabove, exhibits antiviral (Nat. Immun. Cell Growth Regul. 7(3):163-8, 1988; AIDS Res Hum Retroviruses. 8(5):613-23, 1992), and tumoricidal activity (Nature 330(6144):173-6, 1987; J. Clin. Oncol. 13(9):2342-53, 1995; J. Immunol. 161(7):3536-42, 1998.
It has been suggested that AS101, as well as other tellurium-containing immunomodulators, stimulate the innate and acquired arm of the immune response. For example, it has been shown that AS101 is a potent activator of interferon (IFN) (IFN) in mice (J. Natl. Cancer Inst. 88(18):1276-84, 1996) and humans (Nat. Immun. Cell Growth Regul. 9(3):182-90, 1990; Immunology 70(4):473-7, 1990; J. Natl. Cancer Inst. 88(18):1276-84, 1996.)
It has also been demonstrated that AS101, as well as other tellurium-containing immunomodulators, induce the secretion of a spectrum of cytokines, such as IL-1α, IL-6 and TNF-α, and that macrophages are one main target for AS101 (Exp. Hematol. 23(13):1358-66, 1995) and it was found to inhibit IL-10 at the m-RNA level, and this inhibition may cause an increase in IL-12 (Cell Immunol. 176(2):180-5, 1997); J. Natl. Cancer Inst. 88(18):1276-84, 1996).
Other publications describing the immunomodulation properties of AS101 include, for example, “The immunomodulator AS101 restores T(H1) type of response suppressed by Babesia rodhaini in BALB/c mice”. Cell Immunol 1998 February; “Predominance of TH1 response in tumor-bearing mice and cancer patients treated with AS101”. J Natl Cancer Inst 1996 September; “AS-101: a modulator of in vitro T-cell proliferation”. Anticancer Drugs 1993 June; “The immunomodulator AS101 administered orally as a chemoprotective and radioprotective agent”. Int J Immunopharmacol 1992 May; “Inhibition of the reverse transcriptase activity and replication of human immunodeficiency virus type 1 by AS 101 in vitro”. AIDS Res Hum Retroviruses 1992 May; “Immunomodulatory effects of AS101 on interleukin-2 production and T-lymphocyte function of lymphocytes treated with psoralens and ultraviolet A”. Photodermatol Photoimmunol Photomed 1992 February; “Use and mechanism of action of AS101 in protecting bone marrow colony forming units-granulocyte-macrophage following purging with ASTA-Z”. Cancer Res 1991 Oct. 15; “The effect of the immunomodulator agent AS101 on interleukin-2 production in systemic lupus erythematosus (SLE) induced in mice by a pathogenic anti-DNA antibody”. Clin Exp Immunol 1990 March; “Toxicity study in rats of a tellurium based immunomodulating drug, AS-101: a potential drug for AIDS and cancer patients”. Arch Toxicol 1989; “The biological activity and immunotherapeutic properties of AS-101, a synthetic organotellurium compound”. Nat Immun Cell Growth Regul 1988; and “A new immunomodulating compound (AS-101) with potential therapeutic application”. Nature 1987 Nov.
U.S. Pat. No. 4,761,490 discloses a topical formulation of AS101 in petroleum jelly or Oil of Olay, for use as an immunostimulant. U.S. Pat. No. 6,742,381 discloses the use of AS101 in petroleum jelly for treating psoriasis.
In addition to its immunomodulatory effect, AS101 is also characterized by low toxicity. Toxicity tests have shown that LD50 values in rats following intravenous and intramuscular administration of AS101 are 500-1000 folds higher than the immunologically effective dose.
While the immunomodulating effect of tellurium-containing compounds was studied with respect to various aspects thereof, the use of tellurium compounds in the protection of skin against damage caused by ultraviolet radiation has never been suggested nor practiced hitherto.
There is thus a widely recognized need for, and it would be highly advantageous to have, a composition for treatment and protection of the skin against damage caused by ultraviolet radiation having advantages over prior art compositions by inclusion of tellurium containing compounds which prevent the induction of IL-10-induced immunosuppression caused by exposure to ultraviolet radiation.